Pharmaceutical salts of 4&#39;-(9-acridinylamino)-methanesulfon-m-anisidide

ABSTRACT

Pharmaceutical salts of 4&#39;-(9-acridinylamino)-methanesulfon-m-anisidide, methods for their preparation and use of said salts in the form of pharmaceutical compositions as antineoplastic agents.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of copending U.S. applicationSer. No. 129,503, filed Mar. 11, 1980, now abandoned.

SUMMARY AND DETAILED DESCRIPTION

The present invention relates to pharmaceutically acceptableacid-addition salts of 4'-(9-acridinylamino)-methanesulfon-m-anisidide(m-AMSA), which has the structure ##STR1## wherein said salts have arelatively high degree of solubility in water and remain in solution fora sufficient period of time to permit the solution to be introduced intoa mammal. The term "solution" is defined in this invention as a materialwhich is in a liquid fluid state capable of almost completely passingthrough about a 0.22μ millipore filter. Certain of the salts do formtrue solutions; however, this may not always be the case. Morespecifically, the invention relates to pharmaceutically acceptableacid-addition salts of the formula

    m-AMSA.X

wherein X is an acid having a total of from three to six carbon atoms,two to five hydroxy groups and an acidic group which may be a --CO₂ Hgroup or a --OPO₃ H₂ group with the proviso that when the total numberof carbon atoms is three or four, the acidic group is OPO₃ H₂.

The compound X of the formula m-AMSA.X, may be in the D, L or a racemicform. In addition, the salt m-AMSA.X may exist in a solvated form. Allof the foregoing forms are intended to be encompassed by the formulam-AMSA.X.

The preferred acids represented by X are D-gluconic acid, D-glucuronicacid, D-galacturonic acid and β-glycerophosphoric acid which give riseto 4'-(9-acridinylamino)methanesulfon-m-anisidide D-gluconate,4'-(9-acridinylamino)methanesulfon-m-anisidide D-glucuronate,4'-(9-acridinylamino)methanesulfon-m-anisidide D-galacturonate, and4'-(9-acridinylamino)methanesulfon-m-anisidide β-glycerophosphate,respectively.

The present invention also relates to methods for preparing said salts,pharmaceutical compositions utilizing said salts and methods of treatingmammals having certain viral or microbial infections, cancer or a tumorwith said salts, preferably in the form of the disclosed pharmaceuticalcompositions.

The compound 4'-(9-acridinylamino)methanesulfon-m-anisidide, generallyreferred to as m-AMSA, has been found to have a high degree of activityin treating mammals in studies using mice:

"The Experimental Antitumour Properties of Three Congeners of theAcridylmethanesulphonanilide (AMSA) Series," B. F. Cain and G. J.Atwell, Europe. J. Cancer, Vol. 10, pp. 539-549. Pergamon Press (1974);

"Potential Antitumor Agents. 16.4'-(Acridin-9-ylamino)methanesulfonanilides," Bruce F. Cain, Graham J.Atwell and William A. Denny, Journal of Medicinal Chemistry, Vol. 18,pp. 1110-1117 (1975); "Structure-Activity Relationships for ThiolyticCleavage Rates of Antitumor Drugs in the4'-(9-Acridinylamino)methanesulfonanilide Series," Bruce F. Cain,William Robert Wilson and Bruce C. Baguley, Molecular Pharmacology, Vol.12, pp. 1027-1035 (1976);

"Potential Antitumor Agents. 17. 9-Anilino-10-methylacridinium Salts,"Bruce F. Cain, Graham J. Atwell and William A. Denny, Journal ofMedicinal Chemistry, Vol. 19, pp. 772-777 (1976);

"Potential Antitumor Agents. 26. Anionic Congeners of the9-Anilinoacridines," William A. Denny, Graham J. Atwell and Bruce F.Cain, Journal of Medicinal Chemistry, Vol. 21, pp. 5-10 (1978).

The compound m-AMSA is generally prepared by coupling 9-chloroacridineto 4'-aminomethanesulfon-m-anisidide under acid-catalyzed condictionswhich is described in the following references:

"Potential Antitumor Agents. 12. 9-Anilinoacridines," G. J. Atwell, B.F. Cain and R. N. Seelye, Journal of Medicinal Chemistry, Vol. 15, pp.611-615 (1972);

"The Experimental Antitumour Properties of Three Congeners of theAcridylmethanesulphonanilide (AMSA) Series," B. F. Cain and G. J.Atwell, Europ. J. Cancer, Vol. 10, pp. 539-549. Pergamon Press (1974);

"Potential Antitumor Agents. 16.4'-(Acridin-9-ylamino)methanesulfonanilides," Bruce F. Cain, Graham J.Atwell and William A. Denny, Journal of Medicinal Chemistry, Vol. 18,pp. 1110-1117 (1975); "Potential Antitumor Agents. 17.9-Anilino-10-methylacridinium Salts," Bruce F. Cain, Graham J. Atwelland William A. Denny, Journal of Medicinal Chemistry, Vol. 19, pp.772-777 (1976);

"Potential Antitumor Agents. 20. Structure-Activity-Site Relationshipsfor the 4'-(9-Acridinylamino)alkanesulfonanilides," Bruce F. Cain andGraham J. Atwell, Journal of Medicinal Chemistry, Vol. 19, pp. 1409-1416(1976);

"Potential Antitumor Agents. 23.4'-(9-Acridinylamino)alkanesulfonanilide Congeners Bearing HydrophilicFunctionality," Bruce F. Cain, Graham J. Atwell and William A. Denny,Journal of Medicinal Chemistry, Vol. 20, pp. 987-996 (1977). which areincorporated by reference.

Unfortunately, m-AMSA is a compound which is not water soluble. It alsohas been found that the salts of m-AMSA, such as the hydrochloride salt,are also of a low order of solubility in water (see Table I). If thecompound is to be administered parenterally, a solution containing thecompound must be prepared. At present, solutions employingdimethylacetamide as the solvent have been tried; however, the toxicityassociated with this solvent makes this approach very undesirable. Ahost of undesirable, side reactions are associated with the use ofsignificant quantities of dimethylacetamide, see Cancer ChemotherapyReports, No. 16, Feb. 1962, 477-485. In addition, the dimethylacetamideis a potent solvent which presents problems as relates to the tubing andplastic syringes used when administering or storing the solution.

It has been found that certain acids when reacted with m-AMSA give saltshaving high degrees of water solubility. The salts of th presentinvention allow one to prepare solutions of m-AMSA without the aid ofdimethylacetamide. Depending upon the salt, concentration andtemperature, standing may result in certain of the solutions of saltsforming gels. However, a salt need only remain in solution for a periodlong enough for it to be administered to a patient. The stability ofaqueous solutions of certain preferred compounds is given in Table II.

                  TABLE I                                                         ______________________________________                                        Relative Solubility of m-AMSA Salts.sup.a,b                                   Acid           Rel. Solubility as Comp. to H.sub.2 O                          ______________________________________                                        Galacturonic   6133                                                           Glucose-6-Phosphoric                                                                         3785                                                           Gluconic       2815                                                           Ascorbic       1213                                                           β-Glycerophosphoric                                                                     1085                                                           Glucuronic     923                                                            Lactic         890                                                            Glyceric       555                                                            Citric         438                                                            Acetic         234                                                            Propionic      225                                                            Gallic         225                                                            Isethionic     213                                                            Malonic        192                                                            D,L-Malic      165                                                            Succinic       154                                                            d-Tartaric     138                                                            Glutaric       102                                                            Mucic          33                                                             Phosphoric     29                                                             Salicylic      18                                                             Glycolic       18                                                             Benzoic        10                                                             Methane-Sulfonic                                                                             7.5                                                            Gentisic       7.5                                                            Sulfuric       6                                                              Nitric         3                                                              Sulfamic       2.8                                                            Hydrochloric   1.2                                                            Water          1                                                              ______________________________________                                         .sup.a After solution is achieved, certain solutions upon standing set up     like gels. The fact that on standing gels form in certain instances is no     reflected in the table.                                                       .sup.b The values were obtained by adding mAMSA to 0.1 M aqueous              solutions, except gallic acid (0.05M), mucic acid (0.01M), salicylic acid     (0.015M), benzoic acid (0.015M) and gentisic (0.03M).                    

                                      TABLE II                                    __________________________________________________________________________    Stability of Preferred m-AMSA Salts                                                     m-AMSA                                                                        Concentration                                                                         Temperature                                                 m-AMSA Salt                                                                             mg/ml   °C.                                                                             Results                                            __________________________________________________________________________    gluconate 5.2     room temperature                                                                       (a)                                                                             after four days - fluid and                                                   clear to tyndall light.                                                     (b)                                                                             after three weeks - fluid and                                                 clear to ordinary light, haze                                                 by tyndall light.                                gluconate 5.2     5°                                                                              (a)                                                                             after four days - solution                                                    gelled.                                          gluconate 7.4     room temperature                                                                       (a)                                                                             after three days - fluid                                                      and clear to tyndall light.                                                 (b)                                                                             after three weeks - fluid                                                     and clear to ordinary                                                         light, haze by tyndall light.                    gluconate 7.4     5°                                                                              (a)                                                                             after three days - solution                                                   gelled.                                          gluconate 10      room temperature                                                                       (a)                                                                             after 18 hours - fluid and                                                    clear to tyndall light.                                                     (b)                                                                             after 18 days - clear to                                                      ordinary light, haze by                                                       tyndall light.                                   gluconate 10      5°                                                                              (a)                                                                             after 18 hours - solution                                                     gelled.                                                                     (b)                                                                             after 18 days - solution                                                      gelled* with slight                                                           flocculant precipitate.                          glucuronate                                                                             4.97    room temperature                                                                       (a)                                                                             after 18 days - hazy to                                                       tyndall light and some                                                        particles.                                       glucuronate                                                                             4.97    5°                                                                              (a)                                                                             after 18 days - solution                                                      gelled but liquifies on                                                       warming to room temperature                                                   with stirring (haze to                                                        tyndall light and slight                                                      precipitate).                                    β-glycerophosphate                                                                 7.5     room temperature                                                                       (a)                                                                             after three days - fluid and                                                  clear to tyndall light.                                                     (b)                                                                             after three weeks - solution                                                  gelled but became fluid on                                                    shaking (haze to tyndall light).                 β-glycerophosphate                                                                 7.5     5°                                                                              (a)                                                                             after three days - gelled                                                     (warming to room temperature                                                  and shaking gave solution clear                                               to tyndall light).                                                          (b)                                                                             after three weeks - gelled                                                    (warming to room temperature                                                  and shaking gave solution                                                     hazy to tyndall light).                          __________________________________________________________________________     *all foregoing gluconate solutions of lower concentration that gelled at      5° C. could be returned to a fluid state by warming to room            temperature and shaking, at 10 mg/ml this could not be achieved after         storing at 5° C.                                                  

It is also noted that solubility is enhanced by the presence of anexcess of an acid of the formula X' wherein X' is an acid having a totalof from three to six carbon atoms, two to five hydroxy groups and anacidic group which may be a --CO₂ H group or a --OPO₃ H₂ group with theproviso that when the total number of carbon atoms is three or four, theacidic group is OPO₃ H₂.

The acid X' may or may not be the same as the acid used in forming thesalt of m-AMSA. Generally, the same acid is employed to form the salt ofm-AMSA and supply the excess acid, since it is more convenient to usethis approach to prepare the m-AMSA salt with excess acid (X and X' arethe same in this instance). The quantity of excess acid used, whencompared to the m-AMSA salt on a molar basis, is about 0.2 moles toabout 10.0 moles per mole of m-AMSA salt, preferably approximately 1.0moles to approximately 6.0 moles.

The salts are prepared from m-AMSA base and the acid in an inertsolvent. Although up to 10% molar excess of either reagent may beemployed, equimolar proportions of m-AMSA base and the acid arepreferred.

The m-AMSA base and the acid are dissolved in dimethylformamide,dimethylacetamide, methanol, anhydrous ethanol, 95% ethanol, isopropanolor combinations of the solvents at 35° to 100° C. After filtration ofthe solution, the salt is precipitated by addition of another solventsuch as anhydrous ethanol, isopropanol, anhydrous diethyl ether or ethylacetate and/or chilling at 5° to -20° C. for 2 to 24 hours. Thepreferred method is to dissolve the m-AMSA base and acid in anhydrousethanol and dimethylformamide at 70°-100°, in boiling anhydrous ethanolor in boiling methanol. The solution is filtered and the salt separatedfrom the filtrate by the following procedures. Thedimethylformamide-anhydrous ethanol solution (about 70° C.) is dilutedwith anhydrous ethanol; the anhydrous ethanol and the methanol solutionsat 30°-35° C. are diluted with diethyl ether. The product is furtherprecipitated by chilling the filtrates at 5° to -20° C. for 16-24 hours.After collecting the product it is dried under reduced pressure at50°-60° C.

The compounds of the present invention are useful in treating certainviral infections, namely those caused by Avian myeloblastoma or vacciniavirus or certain bacterial infections, namely those caused by Salmonellatypthimurium bacteria.

In addition, compounds of the present invention are usefulantineoplastic agents in the treatment of leukemia, breast cancer andlymphomas in mammals, such as dogs, cats, etc.

The use of m-AMSA in treating leukemia is reported in

1. Dupont, J., et al.--a Phase II trial of m-AMSA in acute leukemia.AACR (abstract C-562) 1981.

2. Goldsmith, M. A., et al.--Phase I study of m-AMSA in patients withsolid tumors and leukemias. Cancer Clinical Trials 3:197-102, 1980.

3. Kahn, S. B., et al.--Combined m-AMSA (NSC 2499) and 5-azacytidine(AZA) in the therapy of relapsed acute leukemia and the acceleratedphase of chronic myeloid leukemia (CML) AACR (abstract C-614) 1981.

4. Land, V. J., et al.--Efficacy and toxicity ofmethanesulfon-m-anisidine, 4'-(9-acridinylamino) 24992) (m-AMSA) inadvanced childhood leukemia. ACCR (Abstract C-471) 1980.

5. Lawrence, H. J., et al.--m-AMSA: a promising new agent in refractoryacute leukemia. AACR (abstract C-471) 1980.

6. Legha, S. S., et al.--Early clinical evaluation ofacridinylaminomethanesulfon-m-anisidide (AMSA) in patients with advancedbreast cancer and acute leukemia. AACR (abstract C-518) 1979.

7. Legha, S. S., et al.--4'-(9-acridinylamino)-methanesulfon-m-anisidide(AMSA): a new drug effective in the treatment of adult acute leukemia.Annals of Internal Medicine, 1980 93 (Part 1): 17-21.

8. McCredie, K. B., et al.--use of a4'-(9-acridinylamino)methanesulfon-m-anisidide (AMSA),cytosine-arabinoside (Ara-C) vincristine prednisone combination(AMSA-OAP) in poor risk patients in acute leukemia. AACR (abstractC-571) 1981;

breast cancer is reported in

1. Buzdar, A. U., et al.--Phase II evaluation of AMSA in combinationwith peptichemio in metastic breast cancer resistant to conventionalchemotherapy. AACR (abstract 724) 1980.

2. Legha, S. S., et al.--Phase II study of4'-(9-acridinylamino)methanesulfon-m-anisidide (AMSA) in metastaticbreast cancer. Cancer Treatment Reports Vol. 63, No. 11-12,November/December 1979.

3. Samal, B. A., et al.--m-AMSA for treatment of disseminated breastcancer. AACR (abstract 175) 1980;

and lymphoma is reported in

1. Cabanillas, F., et al.--Phase II study of AMSA(acridinylaminomethanesulfon-m-anisidide) in lymphoproliferativedisorders. AACR (Abstract 624) 1980.

2. Cabanillas, F., et al.--initial experience with AMSA as single agenttreatment against malignant lympoproliferative disorders. Blood, vol.57, No. 3 (March), 1981.

3. Warrell, Jr., R. P., et al.--Phase II trial of4'-(9-acridinylamino)methanesulfon-m-anisidide (AMSA) in the treatmentof advanced non-Hodgkin's lymphoma. Cancer Treatment Reports Vol. 64,No. 10-11, October/November 1980.

These papers are incorporated by reference.

The preferred route of administration is intravenous and the dosegenerally employed is from about 20 mg to about 500 mg/m² of bodysurface per day for one to five days preferably 30 mg to 100 mg/m² perday for about three days. The procedure may be repeated about everythree weeks.

The compounds of the present invention may also be administered orallyin the form of capsules, tablets, syrups, etc., or rectally in the formof suppositories. Generally, higher doses are employed when using theseroutes, especially orally. Thus, when employing these routes about 20 mgto about 1.0 g/m² of body surface per day for from one to five days,preferably 50 mg to 800 mg/m² per day for about three days is used.

The compounds of the invention, when administered intravenously, aregenerally dissolved in water, sterifiltered, lyophilized and redissolvedat the time of use. Preferably, an excess of acid is present to furtherimprove solubility and minimize the chances of any blockage of the poresduring the sterifiltration step. As excess of an acid is less desirableif the sterilization process does not utilize a microfiltration step.The lyophilized material is dissolved in a non-toxic aqueous vehicleprior to administration. The vehicle may contain buffers, materials, tomake the resultant solution isotonic, preservatives, etc., which arecompatable with the compounds of this invention. Certain ions, such ashalide ion, cause precipitation of the hydrohalide salt of m-AMSA andshould be avoided.

In addition, the compounds of the present invention are orallyadministered, for example, with an inert diluent or with an assimilableedible carrier, or they may be compressed into tablets, or they may beincorporated directly with the food of the diet. For oral therapeuticadministration, the active compounds of this invention may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups and the like. Such compositionsand preparations should contain at least 0.1% of active compound. Thepercentage in the compositions and preparations may, of course, byvaried and may conveniently be between about 5% to about 75% or more ofthe weight of the unit. The amount of active compound in suchtherapeutically useful compositions or preparations is such that asuitable dosage will be obtained. Preferred compositions or preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between about 10 and 200 milligrams of activecompound.

The tablets, troches, pills, capsules and the like may also contain thefollowing: a binder such as gum tragacanth, acacia, corn starch orgelatin; an excipient such as dicalcium phosphate, a disintegratingagent such as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. Various othermaterials may be present as coatings or to otherwise modify the physicalform of the dosage unit, for instance, tablets, pills or capsules may becoated with shellac, sugar or both. A syrup or elixir may contain theactive compounds, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and a flavoring such as cherry ororange flavor. Of course, any material used in preparing any dosage unitform should be pharmaceutically pure and substantially non-toxic in theamounts employed.

Lastly, the compounds of this invention may be administered in the formof a suppository using glycerin, cocoa butter, etc., as a vehicle. Inaddition to the compounds of the invention, preservatives and/orcoloring agents may also be incorporated into the suppository. Theenhanced solubility of the m-AMSA salts may also give certain advantageswhen administered by these routes.

The compounds of this invention may be administered in combination withother antineoplastic agents. The antineoplastics may be derived from thenumerous classes of agents; such as: antibiotic derivatives,doxorubicin, mitomycin, actinomycin, etc.; antiestrogen agents, such astamoxifen; antimetabolites, such as fluorouracil, carmustine, lomustine,methotrexate, mercaptopurine, thioguanine, etc.; cytotoxic agents, suchas bleomycin, cyclophosphamide, busulfan, procarbazine, hyroxyurea,etc.; hormones, such as dromostanolone, ethinyl estradiol, megestrol,prednisone, methyltestosterone, chlorotrianisene, testolactone, etc.;nitrogen mustard derivatives, such as melphalan, chlorambucil,methlorethamine, TESPA, etc.; steroids, such as betamethasone,prednisolone, etc., and other miscellaneous agents, such as vinblastine,vincristine, asparaginase, mitotane, cisplatin, etc. When usingcombinations of two or more neoplastic agents, the dosage of m-AMSA saltmay be reduced. The dosage ranges generally employed for the above citedantineoplastics which may be used with m-AMSA are known to the medicalprofession, see Physicians' Desk Reference, 34th Edition, MedicalEconomics Co. 1980, which is incorporated by reference.

The invention is illustrated by the following examples.

EXAMPLE 1

m-AMSA D-Gluconate

A solution of 3.93 gm of m-AMSA and 5.15 gm of D-gluconic acid-watersolution (38% w/w) in 305 ml of specially denatured 3A anhydrous ethanolat 70°-80° C. is filtered with suction. The filtrate is cooled to30°-35° C. and 100 ml of anhydrous diethyl ether is added with stirring.After chilling to 0°-5° C. with stirring, the mixture is stored about 16hours at 5° C. The product is collected, washed with specially denatured3A anhydrous ethanol and anhydrous diethyl ether (3:1) at 5° C., thenwith several portions of anhydrous ether and dried under reducedpressure at 50°-55° C. to give 3.95 gm of m-AMSA D-gluconate. The saltobtained by this process retains a small amount (about 1% of ethanol).

EXAMPLE 2

m-AMSA D-Galacturonate

A solution of 3.93 gm of m-AMSA and 2.12 gm of D-galacturonic acidmonohydrate in 325 ml of specially denatured 3A anhydrous ethanol at70°-80° C. is filtered with suction. The filtrate is stirred and chilledto 0°-5° C., then stored at -20° C. for about 16 hours. The product iscollected, washed with cold (about -20° C.) specially denatured 3Aanhydrous ethanol, then with anhydrous diethyl ether and dried underreduced pressure at 50°-55° C. to give 3.9 gm of m-AMSA D-galacturonate.The salt obtained by this process retains a small amount about 3% ofethanol.

EXAMPLE 3

m-AMSA D-Glucose-6-phosphate

A mixture of 1.1804 gm of m-AMSA and 0.8576 gm of (91%)D-glucose-6-phosphoric acid monohydrate in 19.3 ml of dimethylformamideis heated on a hot plate until a complete solution is obtained at about100° C. The hot, dark-colored solution is then diluted with an equalvolume of warm (65°-70° C.) specially denatured 3A anhydrous ethanol andfiltered immediately. Additional warm specially denatured 3A anhydrousethanol (about 70° C.) is used to rinse the funnel so that a total of96.5 ml of ethanol is used. The mixture is allowed to cool to about20°-25° C. with occasional swirling of the flask. The mixture is thencooled for several hours at 3°-5° C. and then for a similar period oftime at -18° to -20° C. The solid is collected, washed thoroughly withcold (3°-5° C.) specially denatured 3A anhydrous ethanol, then withanhydrous diethyl ether and dried under reduced pressure at 39°-40° C.to give 1.38 gm of m-AMSA D-glucose-6-phosphate.

EXAMPLE 4

m-AMSA D-Glucuronate

A solution of 3.93 gm of m-AMSA and 2.0 gm of D-glucuronic acid in 325ml specially denatured anhydrous ethanol at 70°-80° C. is filtered withsuction. After cooling to 30°-35° C., 45 ml anhydrous diethyl ether isadded with stirring and chilling to 5° C. After chilling about 16 hoursat 5° C., the salt is collected, washed with cold (0°-5° C.) speciallydenatured 3A anhydrous ethanol, then with anhydrous diethyl ether anddried under reduced pressure at 50° C. to give 4.5 gm of m-AMSAD-glucuronate.

EXAMPLE 5

m-AMSA Gluconate Lyophilized Injectable Formulation

    ______________________________________                                                               per liter                                              ______________________________________                                        1.    m-AMSA Gluconate (11.77 mg/ml*)                                                                      11.77 g                                          2.    Gluconic Acid, 50% Solution                                                                          q.s.                                             3.    Celite 521**           1.5 g                                            4.    Water for Injection, USP q.s. to make                                                                1000 ml                                          ______________________________________                                         *Equivalent to 7.5 mg/ml of mAMSA plus 3% intentional excess.                 **If needed to clarify solution.                                         

Method of Preparation (for 1000 ml):

A. Add sufficient 2 to approximately 900 ml of 4 in a suitable containerto adjust the pH of the solution to approximately 2.2.

B. Add 1 slowly with continuous stirring until 1 completely dissolves.

C. Recheck pH and adjust to 2.3-2.7, if needed, with 2.

D. Add a sufficient amount of 4 to make 1000 ml of solution and mixwell.

E. If necessary, clarify solution with 3 followed by suitable filtrationto remove 3 (Whatman No. 1 filter paper, Millipore AW 19 membrane orequivalent).

F. Sterilize solution by filtration through a previously sterilizedmembrane (Millipore GS or equivalent) using appropriate prefiltration,if necessary.

G. Aseptically fill into previously sterilized vials (10 ml per vial).

H. Stopper vials loosely with rubber lyophilization stoppers andlyophilize in a suitable lyophilizer, (75 mg m-AMSA per vial).

I. At the conclusion of the lyophilization cycle, stopper and cap vials.

EXAMPLE 6

m-AMSA Gluconate Injectable Formulation

    ______________________________________                                                            per 1000 vials                                            ______________________________________                                        m-AMSA gluconate (117.7 mg/vial*)                                                                   117.7 g                                                 ______________________________________                                         *Equivalent to 75 mg of mAMSA + 3% intentional excess.                   

Method of Preparation:

1. Presterilize the m-AMSA gluconate.

2. Fill into appropriate** (10 ml-20 ml) previously sterilized vials.

3. Stopper and cap vials.

EXAMPLE 7

m-AMSA Gluconate Oral Formulation

    ______________________________________                                                          mg/cap   g/1000 caps                                        ______________________________________                                        1.   m-AMSA Gluconate   76.1*   mg   76.2  g                                  2.   Lactose USP Hydrous                                                                              438.8        438.8                                    3.   Polysorbate 80 USP 5.0          5.0                                      4.   Syloid 74 (silica gel)                                                                           10.0         10.0                                     5.   Alcohol SD 3A Anhydrous                                                                          0.07    ml   7.0   ml                                                         530     mg   530   g                                  ______________________________________                                    

Method of Preparation:

A. Dissolve 3 in 5 and add to 4 contained in a suitable blender. Blendthoroughly. Transfer the wet mass onto trays and dry at about 120° F.overnight. Add to 2 and mix well.

B. Screen 1 through a No. 60 screen. Add material from Step A and blendthoroughly. Pass through No. 60 screen and reblend.

C. Fill 530 mg of the powder mixture into No. "O" dark brown opaque hardgelatin capsules.

We claim:
 1. The compound having the name4'-(9-acridinylamino)methanesulfon-m-anisidide β-glycerophosphate.